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Identification of distinct molecular signatures in AIP mutation-positive familial isolated pituitary adenomas

ABSTRACT: The aim of this study was to perform comparative gene expression analysis of AIP mutation-positive, AIP mutation-negative familial and sporadic somatotroph tumours to discover the genes/pathways responsible for the aggressive phenotype. Gene expression analysis was performed on 25 pituitary samples (five normal pituitary, six AIPpos GH, three AIPneg GH, four sporadic GH, two AIPneg familial NFPA and five sporadic NFPA adenomas) using the Affymetrix human Gene Chip HG-U133 Plus 2.0 array.

ORGANISM(S): Homo sapiens

PROVIDER: GSE63357 | GEO | 2018/04/13

REPOSITORIES: GEO

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miR-34a is upregulated in AIP mutated pituitary adenomas and induces octreotide-resistant cell proliferation and growth hormone secretion

Project description:Pituitary adenomas (PAs) are intracranial tumors associated with significant morbidity due to hormonal dysregulation, mass effects and heavy treatment burden. Growth hormone (GH)-secreting PAs (somatotropinomas) cause acromegaly-gigantism. Genetic forms of somatotropinomas due to germline AIP mutations (AIPmut+) have an early onset and are aggressive and resistant to treatment with somatostatin analogs (SSAs), including octreotide. The molecular underpinnings of these clinical features remain unclear. We investigate the role of miRNA dysregulation in AIPmut+ versus AIPmut- PA samples by array analysis. miR-34a and miR-145 were found highly expressed in AIPmut+ vs AIPmut-somatotropinomas. Ectopic expression of AIPmut (p.R271W) in Aip-/- mouse embryonic fibroblasts upregulated miR-34a and miR-145, establishing a causal link between AIPmut and miRNA expression. In PA cells (GH3), miR-34a overexpression promoted proliferation, clonogenicity, migration and suppressed apoptosis, whereas miR-145 moderately affected proliferation and apoptosis. Moreover, high miR-34a expression increased intracellular cAMP, a critical mitogenic factor in PAs. Crucially, high miR-34a expression significantly blunted octreotide-mediated GH inhibition and anti-proliferative effects. miR-34a directly targets Gnai2 encoding Gαi2, a G protein subunit inhibiting cAMP production. Accordingly, Gαi2 levels were significantly lower in AIPmut+ versus AIPmut- PA. Taken together, somatotropinomas with AIP mutations overexpress miR-34a, which in turn downregulates Gαi2 expression, increases cAMP concentration and ultimately promotes cell growth. Upregulation of miR-34a also impairs the hormonal and antiproliferative response of PA cells to octreotide. Thus, miR-34a is a downstream target of mutant AIP that promotes a cellular phenotype mirroring the aggressive clinical features of AIPmut+ acromegaly.

2020-08-18 | GSE140604 | GEO

Proteogenomic Landscape and Clinical Characterization of GH-producing pituitary adenomas/ somatotroph pituitary neuroendocrine tumors

Project description:Proteogenomic Landscape and Clinical Characterization of GH-producing pituitary adenomas/ somatotroph pituitary neuroendocrine tumors

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Proteogenomic Landscape and Clinical Characterization of GH-producing pituitary adenomas/ somatotroph pituitary neuroendocrine tumors

Project description:The clinical characteristics of growth hormone (GH)-producing pituitary adenomas vary across patients. In this study, we aimed to integrate the genetic alterations, protein expression profiles, transcriptomes, and clinical characteristics of GH-producing pituitary adenomas to detect molecules associated with acromegaly characteristics. Targeted capture sequencing and copy number analysis of 36 genes and non-targeted proteomics analysis were performed on fresh-frozen samples from 121 sporadic GH-producing pituitary adenomas. Targeted capture sequencing revealed GNAS as the only driver gene, as previously reported. Classification by consensus clustering using both RNA sequencing and proteomics revealed many similarities between the proteome and the transcriptome. Gene ontology analysis was performed for differentially expressed proteins between wild-type and mutant GNAS samples identified by non-targeted proteomics analysis and involved in G protein–coupled receptor (GPCR) pathways. The results suggested that GNAS mutations impact endocrinological features in acromegaly through GPCR pathway induction. ATP2A2 and ARID5B correlated with the GH change rate in the octreotide loading test, and WWC3, SERINC1, and ZFAND3 correlated with the tumor volume change rate after somatostatin analog treatment. These results identified a biological connection between GNAS mutations and the clinical and biochemical characteristics of acromegaly, revealing novel molecules associated with acromegaly that may affect medical treatment efficacy.

2022-11-25 | GSE213527 | GEO

Differential Gene Expression and Pathway Analysis in Growth Hormone-Secreting Pituitary Tumors According to Granulation Pattern

Project description:This study investigated differential gene expression between granulation patterns in growth hormone (GH)-secreting pituitary tumors, aiming to elucidate novel transcriptomes that explain clinical variances in patients with acromegaly. Transcriptome analysis was conducted on 6 normal pituitary tissues and 15 GH-secreting pituitary tumors, including 9 densely granulated somatotroph tumors (DGSTs) and 6 sparsely granulated somatotroph tumors (SGSTs). We identified 3111 differentially expressed genes (DEGs) in tumors compared to normal pituitaries, with 1117 DEGs unique to a specific granulation within tumors. SGST showed enrichment of neuronal development and acute inflammatory response pathways, along with a significant enhancement of JAK–STAT, phosphatidylinositol 3-kinase, and MAPK signaling. The results suggest that granulation-specific gene expression may underpin diverse clinical presentations in acromegaly, highlighting the potential for further investigation into these transcriptomic variations and their roles in disease pathology, particularly the involvement of genes linked to neuronal development, inflammatory response, and JAK–STAT signaling in SGST.

2024-04-28 | GSE264621 | GEO

Pangenomic classification of pituitary adenomas

Project description:Pituitary neuroendocrine tumors (PitNETs) are common. They are classified in five main histological types: PitNETs of POU1F1 (Pit1) lineage -lactotroph, somatotroph and thyrotroph -, gonadotroph, and corticotroph PitNETs. Pituitary tumorigenesis is poorly understood. We report here a pangenomic characterization of 134 PitNETs from all types, based on exome, genome, transcriptome, miRnome and methylome. Pit1 lineage was associated with a specific epigenetic signature of diffuse DNA hypomethylation, and correlated with expression of Pit1 markers and chromosomal instability. 45% of somatotroph PitNETs showed GNAS mutations. GNAS-wild type somatotroph showed a distinct transcriptome profile, expressing gonadotroph transcription factor NR5A1 (SF1). Sparsely granulated somatotroph PitNETs was classified apart from somatotroph, owing to a thyrotroph transcriptome signature. 43% of corticotroph PitNETs showed USP8 mutations, sharing a low epithelial-mesenchimal transition (EMT) transcriptome signature. Silent corticotroph PitNETs showed a gonadotroph transcriptome signature evoking transdifferentiation, and lost somatostatin target SSTR5 expression.

| EGAS00001003642 | EGA

Transcriptomic effects of medical treatment on gene expression of growth hormone secreting pituitary neruoendocrine tumour biology

Project description:Pituitary neuroendocrine tumours (PitNET) are rare neoplasms of the pituitary gland that can overproduce pituitary hormones or cause headaches and visual impairment due to mass effect. Growth hormone overproducing somatotroph PitNETs cause acromegaly leading to wide range of connective tissue, metabolic and oncologic disorders. The medical treamment of acromegaly is somatostin analogues (SSA) in specific cases combined with dopamine agnoists (DA), but almost half of patients excert SSA resistence and potential causes of this is unknown. The aim of this study was to characterize transcriptomic patterns of somatotroph PitNETs specifically assessing impact of SSA treatment effects. We investigated gene expession on several levels and functional models of GH PitNETs - tumour tissue of patients with and without SSA preoperative treamtment, tumour derived pituisphere model and classically used GH3 cell line treated with SSA.

2022-04-08 | GSE200175 | GEO

Homo sapiens

Project description:Identification of distinct molecular signatures in AIP mutation-positive familial isolated pituitary adenomas

| PRJNA267563 | ENA

Concomitant deletions of tumor suppressor genes MEN1 and AIP are essential for the pathogenesis of the brown fat tumor hibernoma

Project description:Hibernomas are benign tumors with morphological features resembling brown fat. They consistently display cytogenetic rearrangements, typically translocations, involving chromosome band 11q13. Here we demonstrate that these aberrations are associated with concomitant deletions of AIP and MEN1, tumor suppressor genes that are located 3 Mb apart and that underlie the hereditary syndromes pituitary adenoma predisposition and multiple endocrine neoplasia type I. MEN1 and AIP displayed a low expression in hibernomas whereas the expression of genes up-regulated in brown fat-PPARA, PPARG, PPARGC1A, and UCP1-was high. Thus, loss of MEN1 and AIP is likely to be pathogenetically essential for hibernoma development. Simultaneous loss of two tumor suppressor genes has not previously been shown to result from a neoplasia-associated translocation. Furthermore, in contrast to the prevailing assumption that benign tumors harbor relatively few genetic aberrations, the present analyses demonstrate that a considerable number of chromosome breaks are involved in the pathogenesis of hibernoma.

2010-11-24 | GSE19040 | GEO

AIP inactivation leads to pituitary tumorigenesis through defective Gαi-cAMP signaling

Project description:Gene-level expression profiles of 7 Aip knock-out (triplicates from each) and 9 Aip wild-type mouse embryonic fibroblast cell lines were studied using Affymetrix GeneChip Mouse Exon 1.0 ST Arrays

2014-03-05 | GSE37927 | GEO

Gene expression in somatotropic pituitary tumors

Project description:Acromegaly is a severe and life-threatening disease caused by persistent excess of growth hormone (GH) which stimulates the synthesis and secretion of insulin-like growth factor-1 (IGF-1). In the majority (95%) of patients acromegaly is caused by sporadic GH-secreting neuroendocrine pituitary tumor (PitNET). Acromegaly-causing tumors are histologically diverse. The aim was to determine transcriptomic profiles in different histological subtypes and evaluate clinical implication of differential gene expression.

2022-12-01 | E-MTAB-11889 | biostudies-arrayexpress

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